Our proposal is strengthened by our previous extensive experience with the measurement of cognitive impairment in advanced HIV/AIDS, especially those with a history of substance abuse. The proposal builds on the established NEAD cohort already participating in longitudinal studies of HIV-1 infection in Baltimore. The specific aims are: AIM 1: To identify protein markers in CSF that can distinguish progressive from static HIV-associated neurocognitive disorders (HAND) in individuals with a history of substance abuse. Our hypothesis is that CSF protein markers will be able to differentiate the temporal progression of HAND, reflecting underlying pathophysiological processes, particularly the effects of oxidative stress. AIM 2: To identify protein markers in CSF that differentiate individuals who may be at high risk for the development of HAND because of an increased genetic vulnerability to oxidative stress. Our hypthesis is that CSF protein markers will show variability among individuals based on genetic differences in genes which may regulate host response to oxidative stress. This project relies on the careful, serial characterization of the neurocognitive status of individuals chronically infected with HIV-1. Detailed histories of substance abuse will be gathered so that we can fractionate the cohort by the patterns of drug use. We will also explore the role of genetic variability in the regulation of oxidative stress through our collaboration with Dr George Uhl, head of the Molecular Neurobiology group at NIDA. He has expertise in the areas of molecular neurobiology and complex genetics related to addiction